(Circulation. 1999;100:903-909.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Process of Progression of Coronary Artery Lesions From Mild or Moderate Stenosis to Moderate or Severe Stenosis
A Study Based on Four Serial Coronary Arteriograms per Year
From the MUGIC Group: Multicenter Study Group in Gifu University and Affiliated Hospitals (Gifu University School of Medicine, Gifu Municipal Hospital, National Toyohashi-Higashi Hospital, Gifu Prefectural Hospital, and Matsunami General Hospital) on Cardiac Disease.
Correspondence to Hisayoshi Fujiwara, MD, Second Department of Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500, Japan. E-mail gifuim-gif{at}umin.ac.jp
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Abstract |
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Background—The process of progression in coronary artery disease is unknown.
Methods and Results—The subjects were 36 patients with 36
objective vessels with clinically significant progression of
coronary artery disease (
15% per year) in whom 4 serial
coronary arteriograms (CAGs) were performed at intervals of
4 months in a 1-year period. The degree of progression of percent
stenosis between each of 2 serial CAGs was classified as marked
(M: 15%), slight (S: 5% to 14%), and no progression (N: <5%).
From the pattern of progression, the 36 vessels were classified as 14
type 1 vessels with marked progression (N
NM in 13 vessels and
SSM in 1 vessel) and 22 type 2 vessels without marked progression
(SSS in 18 vessels, NSS in 4). Percent stenosis at
the first, second, third, and final CAGs was 44±14%, 46±13%,
46±13%, and 88±10% (P<0.05 versus first CAG) in
type 1 vessels and 44±11%, 50±9%, 59±9%, and 67±9% in type 2
vessels (P<0.05 for second, third, and final CAGs
versus first CAG). Type 1 vessels featured the sudden appearance of
severe stenosis due to marked progression, angina pectoris, or
myocardial infarction (71%) and Ambrose type II eccentric lesions
indicating plaque rupture or thrombi (57%). Type 2 vessels featured
continuous slight progression of stenosis with smooth vessel
walls; angina pectoris (14%) occurred when the percent
stenosis reached a severe level. An increase in serum
C-reactive protein was observed only in the type 2 vessel group, which
suggests a relation between continuous slight progression and
inflammatory change.
Conclusions—Two types of stenosis progression provide a new insight into the mechanism of coronary artery disease.
Key Words: coronary disease • proteins • stenosis • angiography
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Progression of coronary artery disease is seen in 7% to 12% of lesions per year, according to the findings from 2 coronary arteriograms (CAGs) obtained at an
1-year
interval.1 2 3 With acute coronary syndrome,
percent diameter stenosis is considered to be suddenly and
markedly increased due to plaque rupture and thrombus formation.
Meanwhile, plaque itself may also grow without thrombi or plaque
rupture.4 5 In this case, the percent diameter
stenosis would be continuously and slightly increased by
growing plaque volume. Therefore, it is hypothesized that the process
of progression of coronary artery stenosis is
classified as either sudden marked progression or continuous slight
progression. However, the precise course of the above process of
progression is not known because annual serial CAGs were previously
very rare, even in patients with coronary artery disease.
However, serial CAGs are now more common in patients with
restenosis after conventional PTCA or direct PTCA for treatment
of acute myocardial infarction.6 Thus, the purpose of the
present study was to define the process of progression of
coronary artery lesions by observation of vessels (objective
vessels of the present study) that did not undergo PTCA or through
which a guidewire had not passed in patients with 4 serial CAGs per
year for PTCAs for the treatment of lesions in other vessels
(nonobjective vessels of the present study). |
Methods |
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Study Patients
A multicenter study in Gifu University and 4 affiliated hospitals on cardiac disease (MUGIC) was organized. Patients with progression of coronary artery stenosis and their CAGs were selected from computer-stored patient lists, which consisted of
15 000 patients with PTCA performed during the 5-year period
between 1991 and 1995 in these facilities. Joint meetings were held to
retrospectively assess patients who met the following criteria: (1) 4
serial CAGs, performed at 4-month intervals (10 to 14 months before
final CAG, 5 to 9 months before final CAG, within 4 months before final
CAG, and final CAG), over a period of 1 year; (2) 1 major
coronary artery (objective vessel) was present through
which a guidewire had not passed, that had not undergone PTCA or CABG
before the final CAG, and that had not been an infarct-related artery;
(3) serial CAGs were clear for quantitative coronary
angiographic analysis and were performed in the same
projections; and (4) clinically significant progression was defined
as an increase of >15% per year in percent diameter stenosis,
which occurred in lesions of >20% diameter stenosis in
objective vessels at the initial CAG. This definition of a clinically
significant progression was similar to that used in previous
studies.2 7
A total of 486 patients met criteria 1, 2, and 3. From those patients,
36 objective vessels of 36 patients with annual progression that met
the fourth criterion were found (7% incidence of clinically
significant progression) (Table
).
CAGs were performed in these patients at 11±1 months before the final
CAG (first CAG), 7±1 months before the final CAG (second CAG), 3±1
months before the final CAG (third CAG), and as a final CAG. The degree
of progression in percent diameter stenosis in each of the 3
intervals of the 4 serial CAGs (between each of 2 serial CAGs) was
classified as marked progression (M: 15%), slight progression (S:
5% to 14%) and no progression (N: <5%).
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The percent diameter stenosis in 36 vessels with annual progression ranged from 20% to 74% at the first CAG. Therefore, as a control without progression, 50 objective vessels (in 50 patients) with a percent diameter stenosis of 20% to 74% at the first CAG that had changes in percent diameter stenosis of <5% between the first and final CAGs were selected at random from 450 patients without clinically significant progression.
Acute coronary syndrome consists of unstable angina and acute myocardial infarction.8 Acute myocardial infarction was defined as typical chest pain that continued longer than 30 minutes, newly developed ischemic ST-T changes or Q waves, and elevation of the serum creatine kinase level to 3-fold higher than the upper limit of the normal range. Unstable angina was classified as new-onset angina, which was defined as the new development of ischemic chest pain within the month before the final CAG, and chronic unstable (worsening) angina, which was defined as an increase in the severity of symptoms in patients with chronic stable angina.9
Coronary Arteriography
To exclude the effect of coronary arterial
spasms, all patients were administered an intracoronary
injection of nitroglycerin before their CAGs.
Arteriograms of the right and left coronary arteries were
performed in at least 3 and 6 projections, respectively. The best
projection, representing stenosis of the lesion
with progression, was selected and examined for changes in percent
diameter stenosis by quantitative coronary angiographic
analysis by use of a cardiovascular measurement
system (Medical Imaging Systems).10
Coronary arteriograms were reviewed by 2 independent observers experienced in angiographic interpretation and blinded to the clinical data according to the criteria proposed by Ambrose et al.4 Briefly, lesions were classified as concentric lesions, type I eccentric lesions, type II eccentric lesions, and multiple irregularities. Interindividual and intraindividual variabilities in the method for assessing progression were measured with coronary arteries with percent diameter stenosis of <50% and >50% (n=20 in each group). Interindividual variability was 2.5±1.7% in the former and 2.1±1.8% in the latter group. Intraindividual variability was 1.8±1.1% in the former and 2.5±1.5% in the latter group.
Coronary Risk Factors
Risk factors were investigated at the first CAG, including
resting blood pressure, smoking status, presence of diabetes and
obesity, and measurement of serum cholesterol. Family
history of coronary artery disease was also included.
Hyperlipidemia was considered present when the
subject was receiving therapy or when the serum total
cholesterol was 240 mg/dL and/or LDL
cholesterol was 160 mg/dL. Hypertension was considered
present when the subject was receiving therapy, systolic
blood pressure was 140 mm Hg, and/or diastolic
blood pressure was 90 mm Hg. Diabetes was considered
present when the subject was receiving therapy, the subject had an
abnormal glucose tolerance test, or the fasting blood glucose
concentration was 140 mg/dL. Smoking habit was considered present
when the subject smoked a half pack of cigarettes or more per day, and
an ex-smoker was defined as a subject who had stopped smoking for 2
years. Obesity was judged to be present when the body mass index
was 26 kg/m2.
Serum C-Reactive Protein
Serum C-reactive protein (CRP), an indicator of nonspecific
inflammation, was retrospectively examined in all patients at the
first, third, and final CAGs and was compared with the data of 200 age-
and sex-matched healthy volunteers. Data were excluded if the patient
had infectious or collagen disease in which serum CRP was increased. In
patients with acute coronary syndrome, serum CRP at the final
CAG after onset was used only when blood sampling was performed within
5 hours after onset, because serum CRP may be increased secondary to
acute coronary syndrome, especially acute myocardial
infarction. In addition, to define precisely whether an increase of
serum CRP was the cause or the result of plaque rupture with thrombi,
serum CRP was also examined retrospectively in the 72 patients with
acute myocardial infarction, a condition indicative of plaque rupture
with thrombi, and blood sampling was performed within 3 hours after
onset. These patients were selected from the serial patient group with
acute myocardial infarction for 5 years from which subjects were
selected for the present study.
Statistical Analyses
Unpaired Student's t test was used to compare data
between 2 groups. ANOVA was used to compare data among 3 or more
groups. 
2 analysis was used to compare
categorical data. A value of P<0.05 was considered
significant. All data are presented as mean±SD.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Thirty-six objective lesions in 36 patients showed clinically significant progression of >15% per year in percent diameter stenosis. Progression was classified as no progression (N; <5% increase in percent stenosis), slight progression (S; 5% to 14% increase), and marked progression (M;
15% increase). The 36
lesions were classified as 14 type 1 vessels with marked progression
(NNM in 13 vessels and SSM in 1 vessel) and 22 type 2
vessels without marked progression (SSS in 18 vessels and
NSS in 4 vessels) (Figures 1, 2, and 3).
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Characteristics of Patients
As shown in the Table
, patient characteristics and the
characteristics of objective vessels and 2 nonobjective vessels were
similar among patients with type 1 and type 2 vessels and the control
group at the first CAG.
Between the first and final CAGs, 10 (71%) of 14 patients with type 1 vessels, 12 (55%) of 22 patients with type 2 vessels, and 31 (62%) of 50 patients in the control group were administered aspirin. Among patients with type 1 and 2 vessels and in controls, antiplatelet agents were taken in 56%, 68%, and 64%; coumadin in 50%, 45%, and 44%; nitrate in 100%, 100%, and 94%; and calcium antagonist in 86%, 73%, and 78%, respectively. There were no significant differences in the use of these medications among the above 3 groups.
In patients with type 1 and 2 vessels and control subjects, all patients with hyperlipidemia (43%, 50%, and 38% of subjects, respectively) and hypertension (57%, 50%, and 48%, respectively) were treated with cholesterol-lowering drugs and antihypertensive drugs. Patients with diabetes mellitus (36%, 32%, and 34%, respectively) were treated with diet therapy, oral hypoglycemic drugs, or insulin. No significant differences in smoking status, obesity, or family history of coronary heart disease were found among the 3 groups.
Changes in Percent Diameter Stenosis in Objective
Vessels
The results are shown in Figures 1 through 4. In 14 objective type 1 vessels, the
percent diameter stenosis in the first, second, third, and
final CAGs was 44±14%, 46±13%, 46±13%, and 88±10%,
respectively. The degree of progression per year was 44±15%
(range, 22% to 70%). Marked progression was observed between
the third and final CAGs, and the increase in percent diameter
stenosis ranged from 21% to 66% (mean±SD, 41±15%).
In 22 objective type 2 vessels, the percent diameter stenosis
in the first, second, third, and final CAGs was 44±11%, 50±9%,
59±9%, and 67±9%, respectively. The degree of progression per year
was 23±5% (range, 17% to 33%).
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Percent diameter stenosis of the objective vessels was similar between type 1 and type 2 vessels at the first CAG but was significantly greater in type 2 vessels than in type 1 vessels at the third CAG. Percent diameter stenosis at the final CAG was significantly greater in type 1 vessels than in type 2 vessels.
Acute Coronary Syndrome and Lesions of Objective
Vessels
All acute coronary syndromes occurred between the third
and final CAGs. Acute coronary syndrome was noted in 10 of 14
type 1 vessels and in 3 of 22 type 2 vessels. The difference was
significant. In the 10 patients with type 1 vessels, progression
between the third and final CAGs was marked in objective vessels (26%
to 68%) but not in the nonobjective vessels (-1% to 2%). At the
final CAG, percent diameter stenosis of the objective vessels
was severe (80% to 100%) but that of the nonobjective vessels was
mild or moderate (36% to 71% in maximal percent diameter
stenosis of nonobjective vessels). In the 3 patients with type
2 vessels, the progression between the third and final CAGs was slight
in the objective vessels (6% to 11%), but no progression was observed
in the nonobjective vessels (0% to 1%). Percent diameter
stenosis of the objective vessels at the final CAG was severe
(80% to 82%) but that of the nonobjective vessels was mild (36% to
48% in maximal percent diameter stenosis of nonobjective
vessels). Thus, the culprit lesion in acute coronary syndrome
in these patients was not the nonobjective vessels but the objective
vessels.
Percent diameter stenosis of the objective vessels in patients
with acute coronary syndrome was more severe than in patients
without acute coronary syndrome in both type 1 and 2 vessels.
Percent diameter stenosis of the objective vessels in CAGs
before and after the acute coronary syndrome occurred is shown
in Figure 4. In patients with type 1 vessels, percent diameter
stenosis was greatest in acute myocardial infarction (97±4%),
less in new-onset effort angina (89±5%), and least in those with no
clinical events (75±5%) at the final CAG, although it was similar
among the above 3 patient groups at the third CAG (50±20%, 49±9%,
and 38±10%, respectively) (Figure 4). However, in patients
with type 2 vessels, percent diameter stenosis among those with
unstable angina and those with no clinical events was 72±3% and
57±7% at the third CAG and 81±1% and 66±7% at the final CAG,
respectively. The differences between those with unstable angina and
those with no clinical events were significant in each of the third and
final CAGs.
Collaterals from nonobjective vessels to objective vessels were observed only at the final CAGs of 5 patients with type 1 vessels, although the degree of collateral was not rich (poor in 2 patients and moderate in 3 patients). All 5 patients had acute myocardial infarction with typical chest pain. The percent diameter stenosis at the final CAG was highest in 5 type 1 vessels with collaterals (97±4%), less in 9 type 1 vessels without collaterals (83±9%), and least in 22 type 2 vessels without collaterals (69±8%). The rate of progression between the third and final CAGs was similar in type 1 vessels with and without collaterals (50±20% and 45±11%, respectively).
Angiographic Morphology in Objective Vessels
Ambrose type II eccentric lesions, indicating plaque rupture
and/or thrombus formation,4 8 were seen in 8 of 14 type 1
vessels, 4 of 22 type 2 vessels, and 3 of 50 control vessels. However,
in the 3 vessels of control subjects, these lesions were found in each
of 4 serial CAGs. Therefore, the number of vessels in which CAG
findings before and after the appearance of Ambrose type II eccentric
lesions could be observed was 8 in type 1 and 4 in type 2. Ambrose type
II eccentric lesions in type 1 vessels were combined with marked
progression and those in the type 2 vessels with slight progression.
The percent diameter stenosis before the appearance of Ambrose
type II eccentric lesions was similar in type 1 (50±17%) and type 2
(62±9%) vessels. However, the percent diameter stenosis after
their appearance was significantly greater in type 1 (92±8%) than in
type 2 (70±11%) vessels. Except for these vessels, the wall in the
vessels was smooth.
Serum CRP
Serum level of CRP in study subjects was within 0.4 mg/dL of that
measured in 95% of 200 age- and sex-matched healthy volunteers
(0.2±0.1 mg/dL). Serum CRP levels at the first, third, and
final CAGs were 0.2±0.3, 0.1±0.1, and 0.1±0.2 mg/dL in the type 1
group (n=11); 0.4±0.4, 0.4±0.4, and 0.3±0.3 mg/dL in the type 2
group (n=18); and 0.2±0.2, 0.2±0.2, and 0.2±0.1 mg/dL in the control
group without progression (n=40). Serum CRP was significantly higher in
the type 2 group than in the type 1 group or the control group without
progression, although the type 1 and control groups showed similar CRP
levels. Serum CRP was not increased in the 72 patients with acute
myocardial infarction in whom blood sampling was performed within 3
hours after onset of the infarction (0.1±0.2 mg/dL; n=72).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study revealed 2 different types of processes in the progression of coronary artery disease, type 1 and type 2.
Study Limitations
The mean age and sex differences in patients with type 1 and 2
vessels and control patients were similar to those of usual Japanese
patients with coronary heart disease.6 However,
the incidences of multivessel disease and myocardial infarction were
considerably higher in the progression groups than in usual Japanese
patients with coronary heart disease (50% and 30%,
respectively).6 The restenosis rate after PTCA for
treatment of lesions in nonobjective vessels in the progression groups
was the same as the upper limit of the restenosis rate after
PTCA in patients with usual coronary heart disease (30% to
50%).6 However, similarly high incidences were also
observed in the control group without progression. In addition, the
incidence of objective vessels with progression of stenosis of
7% per year in the present study was similar to that of previous
studies.1 2 3 Therefore, these high incidences are
independent of the progression of stenotic lesion in the
objective vessels, although they are special features of patients with
4 serial CAGs per year.
If the percent diameter stenosis reached a moderate or severe level at the final CAG, PTCA was performed in all vessels in the present study. This study limitation explains why all of the marked progression in type 1 vessels was seen only between the third and final CAGs. There were no fatal cases in the present serial CAG study. It is likely that the absence of fatal cases has underestimated the frequency of patients with severe stenosis, especially in type 1 vessels with rapid and marked progression.
Mechanism of Slight and Marked Progression in Type 1 and Type
2 Vessels
Ambrose type II eccentric lesions were seen in 57% of type
1 vessels and 18% of type 2 vessels. The former was associated with
marked progression and the latter with slight progression. CAG is not a
precise method to detect plaque rupture or thrombi. Therefore, the
presence of Ambrose type II eccentric lesions generally indicates
thrombosis or plaque rupture, but its absence does not disprove the
presence of small thrombi or plaque rupture.4 8 The smooth
vessel wall in vessels with continuous slight progression of
stenosis suggests a general growth of the plaque volume itself.
This is supported by the findings of Flugelman et al11
that smooth muscle cell proliferation may lead to gradual plaque
expansion and thereby to luminal narrowing and unstable angina.
However, this angiographic finding of a smooth vessel wall does not
disprove the presence of small thrombi due to plaque rupture or
endothelial damage. Therefore, the mechanism of sudden
marked stenosis progression is probably large thrombi due to
plaque rupture and/or endothelial damage and that of
continuous slight progression is the growth of plaque volume itself or
small thrombi due to plaque rupture and/or endothelial
damage.
A relationship between serum CRP and atherosclerosis or acute coronary syndrome has been reported.12 13 14 However, it remains unknown whether an increase in CRP is related to types of progression or the onset of plaque rupture with thrombi and acute coronary syndrome. In the present study, serum CRP was higher in patients with type 2 vessels than those with type 1 vessels or control patients without progression. This suggests that inflammatory change may be involved in one of the mechanisms of gradual progression in coronary stenosis. Meanwhile, there was no evidence of increased serum CRP at the early stage of acute myocardial infarction, a sign of plaque rupture with thrombi. Thus, plaque rupture with thrombi and/or marked progression is independent of the preceding increased level of serum CRP. An increase of serum CRP in acute coronary syndrome may be the result rather than the cause. Recently, Torzewski et al14 reported tissue CRP in early atherosclerotic lesions of human coronary arteries. Further investigation of the difference in tissue CRP localization among coronary arteries with type 1, type 2, and no stenosis progression is warranted.
Pathophysiological Role of Type 1 and Type
2 Vessels
Generally, acute coronary syndrome depends on the severity
of the percent diameter stenosis and the poorness of collateral
flow.8 15 This was confirmed by the present findings.
Acute coronary syndrome occurred with both marked progression
of type 1 vessels and slight progression of type 2 vessels when the
percent diameter stenosis reached a severe level and the
collateral circulation was not rich.
In the present study, the incidence of acute coronary syndrome was higher in type 1 vessels than in type 2 vessels. Acute myocardial infarction and total or subtotal occlusion were not seen in type 2 vessels but only in type 1 vessels. However, percent diameter stenosis was lower in type 2 vessels than in type 1 vessels at the final CAG, and PTCA was performed in most of the type 2 vessels, as well as the type 1 vessels at the final CAG. Therefore, no information on the natural course of type 2 vessels after the final CAG was obtained. In type 2 vessels, slight stenosis progression may continue after the final CAG because the feature is continuous slight progression, and acute coronary syndrome may appear when the percent diameter stenosis reaches a more severe level.
In vessels with clinically significant progression for 1 year, most of the marked progression occurred in vessels that previously had no progression rather than in vessels that previously had slight progression. However, this does not mean that the incidence of marked progression occurring in vessels that previously showed no progression is higher than that in vessels that previously had slight progression in all patients with and without significant progression for a year, because the incidence of significant progression for 1 year was only 7% in the present study.
In patients with type 1 vessels, marked stenosis progression
with and without acute coronary syndrome appeared suddenly
primarily in vessels with smooth vessel walls and without preceding
progression. There was no evidence of a preceding increase in serum
CRP. Therefore, it is difficult to predict sudden marked
stenosis progression and acute coronary syndrome. In
patients with type 2 vessels, serum CRP was increased, which suggests
that serum CRP may be one of the predictors for type 2 vessels. Percent
diameter stenosis at the third and final CAGs was greater in
patients with new-onset angina than in patients without it. The degree
of progression between the third and final CAGs was similar in both.
This suggests that the appearance of new-onset angina depends on the
preceding percent diameter stenosis. Because the feature of
type 2 vessels was a continuous slight progression, the presence of
SS or S and moderate stenosis (70% diameter
stenosis) would predict that after several months, the percent
diameter stenosis reached a severe level as the result of
further slight progression, and new-onset angina may occur. This
speculation suggests a reason for preventive PTCA in treatment of
lesions with moderate stenosis without angina in type 2
vessels. Thus, prediction of acute coronary syndrome is
difficult in type 1 vessels but may be possible in type 2 vessels.
In conclusion, the concept of type 1 and type 2 vessels provides important information on the progression of coronary artery disease.
Received March 22, 1999; revision received May 19, 1999; accepted June 2, 1999.
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U. E. Heidland and B. E. Strauer Left Ventricular Muscle Mass and Elevated Heart Rate Are Associated With Coronary Plaque Disruption Circulation, September 25, 2001; 104(13): 1477 - 1482. [Abstract] [Full Text] [PDF]
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K. Ohtsuki, M. Hayase, K. Akashi, S. Kopiwoda, and H. W. Strauss Detection of Monocyte Chemoattractant Protein-1 Receptor Expression in Experimental Atherosclerotic Lesions: An Autoradiographic Study Circulation, July 10, 2001; 104(2): 203 - 208. [Abstract] [Full Text] [PDF]
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